Category: Published Research

Categories
Featured Published Research Uncategorized

Coronavirus (COVID-19)

Here’s the latest on the Pine Street Foundation’s research on coronavirus (COVID-19).

RESEARCH PRESENTATION (May 14, 2020)
Michael McCulloch, LAc, MPH, PhD, the Pine Street Foundation’s Research Director, recently gave a presentation about COVID-19:

RESEARCH PRESENTATION (April 15, 2020)
Michael McCulloch, LAc, MPH, PhD, the Pine Street Foundation’s Research Director, recently gave a presentation about COVID-19:

RESEARCH PRESENTATION (March 19, 2020)
Michael McCulloch, LAc, MPH, PhD, the Pine Street Foundation’s Research Director, recently gave a presentation about COVID-19:

Click here for the slides used in this presentation.

Categories
Published Research

Omega-3 & Prostate Cancer Risk

JNCIIn 2013, the prestigious Journal of the National Cancer Institute published a paper purportedly concluding that fish oil supplementation increased risk of prostate cancer. In response, we have detailed the scientific reasons why the results of that paper were unlikely to be valid, particularly since they contradict current knowledge on this topic. The Journal of the National Cancer Institute accepted our paper and published it in 2014.

Please contact us to receive a copy of our paper.

Formal Citation:
McCulloch, MF, et al. (2014). “RE: Serum phospholipid fatty acids and prostate cancer risk in the SELECT trial.” Journal of the National Cancer Institute.

Categories
Published Research

Study Abstracts: Pine Street 10 Year Survival Studies

If you would like to receive a complete copy of these studies, please contact us and we will send you a copy via email.

Lung Cancer Survival With Herbal Medicine & Vitamins In A Whole-Systems Approach: 10-Year Follow-Up Data Analyzed With Marginal Structural Models and Propensity Score Methods

McCulloch MF, Broffman M, van der Laan M, Hubbard A, Kushi L, Kramer A, Gao J, Colford JM: Lung Cancer Survival With Herbal Medicine & Vitamins In A Whole-Systems Approach: 10-Year Follow-Up Data Analyzed With Marginal Structural Models and Propensity Score Methods. 2011. [Epub ahead of print, PMID 21964510] Integrative Cancer Therapies.

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21824893

Abstract: Complementary and alternative medicines are used by up to 48% of lung cancer patients but have seen little formal assessment of survival efficacy. In this 10-year retrospective survival study, the authors investigated Pan-Asian medicine + vitamins (PAM+V) therapy in a consecutive case series of all non-small-cell lung cancer patients (n = 239) presenting at a San Francisco Bay Area Chinese medicine center (Pine Street Clinic). They compared short-term treatment lasting the duration of chemotherapy/radiotherapy with long-term therapy continuing beyond conventional therapy. They also compared PAM+V plus conventional therapy with conventional therapy alone, using concurrent controls from the Kaiser Permanente Northern California and California Cancer Registries. They adjusted for confounding with Kaplan-Meier, Cox regression, and newer methods – propensity score and marginal structural models (MSMs), which when analyzing data from observational studies or clinical practice records can provide results comparable with randomized trials. Long-term use of PAM+V beyond completion of chemotherapy reduced stage IIIB deaths by 83% and stage IV by 72% compared with short-term use only for the duration of chemotherapy. Long-term PAM+V combined with conventional therapy reduced stage IIIA deaths by 46%, stage IIIB by 62%, and stage IV by 69% compared with conventional therapy alone. Survival rates for stage IV patients treated with PAM+V were 82% at 1 year, 68% at 2 years, and 14% at 5 years. PAM+V combined with conventional therapy improved survival in stages IIIA, IIIB, and IV, compared with conventional therapy alone. Prospective trials using PAM+V with conventional therapy for lung cancer patients are justified.

Colon Cancer Survival With Herbal Medicine & Vitamins In A Whole-Systems Approach: 10-Year Follow-Up Data Analyzed With Marginal Structural Models And Propensity Score Methods

McCulloch MF, Broffman M, van der Laan M, Hubbard A, Kushi L, Abrams DI, Gao J, Colford JM: Colon Cancer Survival With Herbal Medicine & Vitamins In A Whole-Systems Approach: 10-Year Follow-Up Data Analyzed With Marginal Structural Models And Propensity Score Methods. 2011. Sep 30. [Epub ahead of print, PMID 21964510] Integrative Cancer Therapies.

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21964510

Abstract: Although localized colon cancer is often successfully treated with surgery, advanced disease requires aggressive systemic therapy that has lower effectiveness. Approximately 30% to 75% of patients with colon cancer use complementary and alternative medicine (CAM), but there is limited formal evidence of survival efficacy. In a consecutive case series with 10-year follow-up of all colon cancer patients (n = 193) presenting at a San Francisco Bay-Area center for Chinese medicine (Pine Street Clinic, San Anselmo, CA), the authors compared survival in patients choosing short-term treatment lasting the duration of chemotherapy/radiotherapy with those continuing long-term. To put these data into the context of treatment responses seen in conventional medical practice, they also compared survival with Pan-Asian medicine + vitamins (PAM+V) with that of concurrent external controls from Kaiser Permanente Northern California and California Cancer Registries. Kaplan-Meier, traditional Cox regression, and more modern methods were used for causal inference-namely, propensity score and marginal structural models (MSMs), which have not been used before in studies of cancer survival and Chinese herbal medicine. PAM+V combined with conventional therapy, compared with conventional therapy alone, reduced the risk of death in stage I by 95%, stage II by 64%, stage III by 29%, and stage IV by 75%. There was no significant difference between short-term and long-term PAM+V. Combining PAM+V with conventional therapy improved survival, compared with conventional therapy alone, suggesting that prospective trials combining PAM+V with conventional therapy are justified.

 

Categories
Published Research

Complementary & Alternative Medicine For Lung & Colon Cancer

In the autumn of 2011, we published the Pine Street Survival Study, our landmark lung and colon cancer survival study research papers. Both papers were published in one of the leading journals focusing on Complementary and Alternative Medicine (CAM) specific to the needs of people with cancer: Integrative Cancer Therapies.

Click here to read the full study abstracts.

Click here to download the full lung cancer study.

Click here to download the full colon cancer study.

In our study, we looked at whether complementary and alternative medical therapy in combination with standard treatments helped extend survival in people with lung and colon cancers. The treatments being examined combined Chinese herbal medicine, vitamins, acupuncture, exercise, dietary guidance, and meditation into a comprehensive approach that in research is called a “Whole Systems” protocol.

In conducting this study, the Pine Street Foundation collaborated with scientists at the University of California Berkeley, University of Cali- fornia San Francisco, Kaiser Permanente, and the California Cancer Registry. Pine Street’s Clinical Director, Michael Broffman, led data collection efforts and Research Director, Michael McCulloch, designed the data analysis, which involved a novel approach that had not yet been done before with CAM studies of cancer treatment.

DATA SOURCES
The primary data source being used for the Pine Street Foundation’s Survival Study is a large database developed from ten years of follow- up records on patients treated between 1989 and 1993 at the Pine Street Clinic in San Anselmo, California. This database contains follow- up results on 235 patients with lung cancer and 193 patients with colon cancer. Because these data were recorded in a consecutive case series, they contain the records of all patients with these conditions treated by the Pine Street Clinic. This is important because the survival data from this set of patients are a complete representation of the treatment experience at the Pine Street Clinic with these patients, and not sim- ply the hand-picked “best case” records often seen in studies of CAM therapies.

The common variables examined for each patient included how long patients received a specific therapy as well as specific dosage schedules of herbal-vitamin products. Data have also been collected on the most important characteristics of patients treated, including age, gender, biopsy results (cell type), stage of disease, type of conventional treatment received, and ethnicity. This allowed for the analysis of the impact of treatment protocol on overall survival.

Using these data, survival among the Pine Street Clinic patients – those using CAM – was compared to survival of patients who did not use CAM. Those comparison patients were obtained from data from local Kaiser Permanente hospitals as well as from the National Cancer In- stitute’s Surveillance, Epidemiology, and End Results (SEER) database.

RESULTS OF THIS STUDY
Patients with both lung and colon cancers who used herbal and vitamin therapy had significantly longer survival than carefully matched controls whose records were obtained from local cancer registries:

» In patients with lung cancer, combination therapy reduced the risk of death in stage IIIA patients by 46%, stage IIIB by 62%, and stage IV by 69%, compared with conventional therapy alone.
» In patients with colon cancer, combination therapy reduced the risk of death in stage I by 95%, stage II by 64%, stage III by 29%, and stage IV by 75%, compared with conventional therapy alone.

Patients with advanced (stage IIIB and IV) lung cancer who continued with long-term use of herbal and vitamin therapy after treatment survived significantly longer than those who used it only short-term during their chemotherapy programs:

» Long-term use of herbal/vitamin therapy beyond completion of chemotherapy reduced stage IIIB deaths by 83% and stage IV by 72%, compared with short-term use only for the duration of chemotherapy.

For colon cancer patients, however, there was no significant difference in survival between people using CAM short-term versus long-term.

WHY THIS STUDY IS IMPORTANT
Large numbers of people throughout the United States – as many as 36% of adults – are using complementary and alternative medicine. However, there are very few published papers that specifically examine one of the most important questions patients diagnosed with cancer ask: Will combin- ing complementary and alternative medicine together with my conventional therapies help me live longer? Our papers provide preliminary data suggesting that the approach used in our Pine Street Survival Study (a comprehensive combination of herbal medicine, antioxidants, vitamins, exer- cise, healthful eating, and stress reduction) can significantly improve longevity when used in concert with conventional treatments.

If you would like to receive a complete copy of these studies, please contact us and we will send you a copy via email when we have permission from the publisher to do so.

 

Categories
Featured Published Research

Paper Published: Scent Identification in Criminal Investigations and Prosecutions

Scent lineups are a powerful tool in the investigation of crimes. With proper procedures, both forensic and judicial, scent lineups can be valuable evidence for a jury to consider. Unfortunately, many courts have been willing to admit poorly conducted procedures, even if giving lip service to the fact that the scent lineup was deficient by saying that its admission was harmless error. The tendency of some courts to view scent lineups as an extension of scent tracking has resulted in admission of scent lineup evidence under inappropriate standards. Tracking cases have set foundational requirements from long-held social and judicial assumptions about the accuracy of dogs. Although no specific set of training procedures or testing protocols need be imposed for the conduct of scent lineups, protocols with elements that have produced highly reliable results should be developed by law enforcement authorities and insisted upon by courts. The authors believe that scent lineups under such protocols can now satisfy the Daubert standard for admissibility of scientific evidence, though perhaps not the Frye standard (because of the lack of general acceptance in the scientific community). Because the possibility of a false identification cannot be completely eliminated, corroboration by other evidence should be required, probably at a clear and convincing level. This is the first every systematic review critically evaluating all the known scientific evidence for the use of canine scent detection in law enforcement

Click here to read the entire paper.

Categories
Canine Scent Detection Published Research

Canine Scent Detection: Breast and Lung Cancer

Diagnostic Accuracy of Canine Scent Detection of Lung and Breast Cancers in Exhaled Breath

The following research was published in the March 2006 issue of Integrative Cancer Therapies, a peer-reviewed journal.

Download a full, free copy of this study by clicking here: PDF [104kb]

Precisión del diagnostico de Detección Canina a través del olfato en las fases tempranas y terminales del cáncer de mama y de pulmón: PDF [258kb]

ABOUT THIS RESEARCH, BRIEFLY
Lung cancer, when symptoms arise, is usually diagnosed at Stage III or IV, when the prognosis is rarely good. Treatment is significantly more effective at early stages (I or II) when the tumor is smaller and has not yet spread. Detecting lung cancer in its early stages is difficult, so therefore developing a feasible and effective early detection method is the subject of a considerable amount of research around the world. In terms of breast cancer, while detection at early stages is comparatively easier, finding methods to detect it even earlier are worthwhile.

Continue reading “Canine Scent Detection: Breast and Lung Cancer”
Categories
Published Research

Chinese Herbal Medicine and Chemotherapy in the Treatment of Hepatocellular Carcinoma: A Meta-analysis of Randomized Controlled Trials

By Xiaojuan Shu, MPH (candidate), Michael McCulloch, LAc, MPH, Hang Xiao, MPH, PhD, Michael Broffman, LAc, and Jin Gao, MD, PhD 

Click here to download this study (including tables) in PDF format.

BACKGROUND
Hepatocellular carcinoma (HCC), one of the most common malignancies worldwide, is highly resistant to standard therapy. It is unclear whether chemotherapy, arte- rial embolization, or arterial chemoembolization improve survival advantage enough to justify their high toxicity. Treatment with Chinese herbal medicine has been explored, combining herbs that stimulate host immune response with those that have cytotoxic activity against HCC cells. The au- thors sought to evaluate the effectiveness of Chinese herbal medicine combined with chemotherapy. The hypothesis was that Chinese herbal medicine added to chemotherapy for the treatment of HCC would improve survival and tumor re- sponse, when compared to treatment with chemotherapy alone. Methods: The authors searched the databases TCMLARS, PubMed, and EMBASE as well as the bibliogra- phies of studies identified in the systematic search for po- tentially relevant titles or abstracts of studies in any language. They retained those that (1) treated only HCC pa- tients, (2) were described as randomized or reported that there was no statistical difference between treatment groups, (3) gave patients either Chinese herbal medicine therapy combined with chemotherapy in the treatment group or chemotherapy alone in the control group, and (4) provided data on the number of enrolled subjects and re- sponders and nonresponders for tumor response and sur- vival. The authors used random effects meta-analysis to combine data. Results: Twenty-six studies representing 2079 patients met the inclusion criteria. Chinese herbal medicine combined with chemotherapy, compared to chemotherapy alone, improved survival at 12 months (relative risk [RR], 1.55; 95% confidence interval [CI], 1.39-1.72; P < .000), 24 months (RR, 2.15; 95% CI, 1.75-2.64; P < .000), and 36 months (RR, 2.76; 95% CI, 1.95-3.91; P < .000). Tumor re- sponse increased (RR, 1.39; 95% CI, 1.24-1.56; P < .000). Conclusions: These findings provide promising evidence that combining Chinese herbal medicine with chemotherapy may benefit patients with HCC. Because of the low quality of these studies, these findings should be confirmed through conducting high-quality, rigorously controlled trials.

INTRODUCTION
Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer worldwide, with increasing incidence.1 The incidence ranges from 1 to 4 cases per 100 000 population in Western Europe and North America to 50 to 150 cases per 100 000 population in parts of Asia and Africa, where HCC is responsible for a large pro- portion of cancer deaths.2 Its treatment remains a con- troversial issue, despite the progress that has been made during the past decades, as most HCC patients are diagnosed at late stages and receive only palliative treatments not intended to extend survival.1 Untreated patients with advanced disease have a 1- year survival rate of 29%, a 2-year survival rate of 16%, and a 3-year survival rate of 8%.3

Arterial embolization, chemoembolization, and arterial chemotherapy are the major procedures in chemotherapy. Arterial embolization or chemoemboli- zation is a technique combining intra-arterial chemo- therapy and selective ischemia and was developed as an alternative to conventional systemic or intra-arterial chemotherapy. It is intended to induce tumor necrosis through administration of chemotherapy and an embolizing agent directly into the tumor by way of the feeding artery. The cytotoxic effect of arterial occlu- sion can be potentiated by labeling the infusion with radioactive isotopes or by adding cytotoxic drugs. Arterial embolization or chemoembolization includes procedures such as transcatheter arterial chemo- embolization, transarterial embolization, hepatic arterial chemoembolization, and hepatic arterial embolization. Arterial chemotherapy is not aimed to achieve arterial occlusion. It includes procedures such as transarterial infusion, hepatic arterial infusion, and intravenous chemotherapy. However, these proce- dures are associated with their own potentially life- threatening toxicities and complications, such as severe postembolization syndrome, hepatic insuffi- ciency, abscess, or infarction.4 In addition, they have shown only slightly improved survival or no survival advantages in previous studies.5-7 Meta-analysis of randomized controlled trials of treatment with chemoembolization or embolization has shown only a modest advantage in 2-year survival for patients with unresectable HCC, compared with conservative man- agement.8 The same meta-analysis revealed that tamoxifen provided no advantage in 1-year survival.8 Since the prognosis with existing therapy is so poor, we sought to evaluate the clinical evidence for effective- ness of Chinese herbal medicine in combination with systemic chemotherapy for the treatment of HCC.

In China, herbal medicine is frequently combined with chemotherapy in the treatment of liver cancer, usually in formulas that combine various Chinese herbs into one treatment strategy. In this meta-analysis, we sought to assess the effectiveness of this therapy for HCC by analyzing data from studies that compared treatment with Chinese herbal medicine combined with chemotherapy to treatment with chemotherapy alone.

METHODS

Systematic Search
Retrieval of studies in all languages was performed through systematic searching of the databases TCMLARS (1984-August 2004; www.cintcm.com), PubMed (1966-August 2004; www.pubmed.gov), and EMBASE (1974-August 2004; www.embase.com) using the keywords liver cancer, chemotherapy, Chinese medicine, and randomized controlled trials. We also searched the bibliographies of review papers and published ran- domized controlled trials identified in our systematic search.

Criteria for Inclusion
To be included in this meta-analysis, a study had to ful- fill the following criteria: (1) only patients with HCC were included, (2) studies were described as random- ized or had the design elements of quasi-randomized studies (studies did not mention adoption of random- ization but reported there was no statistical difference between 2 groups), (3) HCC patients were given ei- ther Chinese herbal medicine therapy in combination with chemotherapy in the treatment group or chemo- therapy alone in the control group, and (4) authors provided necessary data on the number of responders and nonresponders for the end points of tumor re- sponse and survival sufficient to calculate relative risks (RRs) and 95% confidence intervals (CIs).

Criteria for Exclusion
Randomized controlled trials were excluded if they (1) were not described as randomized or quasi- randomized, (2) did not provide information con- cerning survival or tumor response, (3) included patients with cholangiocellular carcinomas or liver metastases of primary cancers other than liver, (4) did not contain an experimental arm treated with Chinese medicine combined with chemotherapy and control arm treated with chemotherapy alone, or (5) were du- plicate publications of other studies previously identi- fied in our systematic search. Decisions on whether to include or exclude trials and how to group studies for analysis by end points reported were made before conducting the meta-analysis.

Criteria for Combinability
Since there is no successful standard treatment for HCC, there are few published trials using exactly the same chemotherapy treatments and same Chinese herbal formula. As has been done in previous meta- analyses of chemotherapy for HCC, we combined studies in which patients in the treatment group were treated with the new therapy being evaluated and those in the control group were treated with standard chemotherapy alone.7-9 We also sought to separately meta-analyze any subgroups of studies that all used the same herbal combination.

Data Collection and Abstraction
Two reviewers (X.S. and M.M.) independently re- viewed the retained studies. Since prior work has shown that blinding during study selection and data extraction does not result in either a clinically or a sta- tistically significant effect on the summary effect mea- sure of a meta-analysis,10 we chose a nonblinded design for data extraction.

Analysis of Outcomes
The primary outcome of interest was the proportion of patients surviving at 6, 12, 24, and 36 months. The secondary outcome of interest was tumor response.

Survival. We calculated survival using the propor- tion of subjects surviving among the total number of  subjects, separately for each treatment group. The ratio for improvement in survival at each time point was calculated as the proportion of subjects alive in the Chinese herbal medicine combined with chemother- apy group divided by the proportion of subjects alive in the chemotherapy-only group.

Objective tumor response. We selected studies that reported tumor response using the World Health Organization scale.11 Following a method used in a previous meta-analysis of studies treating HCC patients with chemotherapy,12 we calculated tumor response as any response (complete response plus partial response) divided by the total (complete response plus partial response plus no change plus progressive disease), separately for each treatment group. The RR of tumor response was calculated as the probability of any tumor response in the herbal medicine combined with chemotherapy group divided by the probability of any tumor response in the chemotherapy-only group.

Pooled analysis. We used the Stata statistical software package (version 8.0; Stata Corp, College Station, Tex) for data management and analysis. All analyses were performed on an intention-to-treat basis. We used the random effects method to calculate pooled treatment effects.13 An RR value greater than 1.0 was considered to be consistent with a beneficial effect of Chinese herbal medicine combined with chemother- apy (vs chemotherapy alone) in the treatment of patients with HCC.

Qualitative Analysis

Study quality. To evaluate study quality, we used the Jadad scale, a validated 5-point scale developed to eval- uate the quality of reporting in studies included in a meta-analysis.14,15 The scale assigns a score of 0 or 1 for each of the following quality criteria, whether (1) the study was described as randomized, (2) the authors reported the method of randomization, (3) the use of blinding was reported, (4) the method for conceal- ment of allocation was reported, and (5) authors accounted for withdrawals and dropouts. Thus, a highest-quality study would receive a score of 5 and a lowest-quality study a score of 0.

RESULTS

Selection of Trials
After an initial screening of titles and abstracts, 385 potentially relevant clinical trials of HCC were identified. We then performed a second screening of these 385 studies and retained 126 published full papers, which were randomized controlled trials assessing Chinese herbal medicine in the treatment of HCC. After fur- ther evaluation, we excluded 9 studies because of nonrandomization, 13 studies because they lacked rel- evant end points, 24 studies because other cancers were included, 51 studies because they were missing either a qualified experimental group or controlled group, and 3 studies because they were duplicate pub- lications of other studies previously identified in our systematic search. This yielded a total of 24 random- ized controlled trials and 2 quasi–randomized con- trolled trials, which were identified as meeting protocol-specified inclusion criteria, totaling 2079 patients (Tables 1 and 2).

Treatment Effectiveness
Chemotherapy combined with Chinese herbal medi- cine, compared with chemotherapy alone, signifi- cantly improved survival at 12 months (RR, 1.55; 95% CI, 1.39-1.72; P < .000; Figure 1), 24 months (RR, 2.15; 95% CI, 1.75-2.64; P < .000; Figure 2), and 36 months (RR, 2.76; 95% CI, 1.95-3.91; P < .000; Figure 3). Tu- mor response was also significantly improved (RR, 1.39; 95% CI, 1.24-1.56; P < .000; Figure 4). There were no reliable data indicating significant survival improve- ment at 6 months since there was significant between- study heterogeneity (Table 3; figure not shown).

We identified 2 studies that used the exact same herbal formula (Hua Chan Su) and conducted a sepa- rate meta-analysis.16,17 The result also showed survival benefits of Hua Chan Su at 12 months (RR, 1.67; 95% CI, 1.38-2.02; P < .000; Table 3; figure not shown). It should be noted that Hua Chan Su contains bufotoxin, a digoxin-like substance that must be pro- vided in carefully measured dosages to avoid cardiac glycoside toxicity.

A Chinese-English translation table is provided as an appendix, which identifies the original names of herbal formulas as identified in included studies and the names as translated into English.

CONCLUSIONS
Our meta-analysis data suggest promising evidence that Chinese herbal medicine in the treatment of HCC may have potential therapeutic value. Herbal medicine combined with chemotherapy for the treat- ment of HCC can improve survival at 12, 24, and 36 months when compared with chemotherapy alone. There is additional evidence that 6-month survival may also be improved; however, this finding is limited by the presence of between-study heterogeneity. Tu- mor response was also improved by the addition of Chinese herbal medicine to chemotherapy.

In a separate meta-analysis of the only 2 studies using the exact same herbal medicine, Hua Chan Su, we found that 12-month survival was also increased.16,17

Limitations

Publication bias. We found evidence for publication bias in the data for meta-analysis of survival at 6 and 12 months for all herbal formulas combined. We also found evidence for publication bias in the data for meta-analysis of tumor response.

Research techniques used in Chinese studies. Because the studies we found were of generally poor quality, we are unable to make definite conclusions from our data. Published studies from China were found to be more highly condensed than typical articles published in the Western literature, with key details of study design omitted, especially details concerning blinding of subjects and clinicians. In addition, since most stud- ies did not describe subject withdrawals or dropouts, it is not possible to adjust the analysis for censoring, and therefore pooled estimates of survival should be inter- preted with caution. However, inadequate reporting of specific details of randomization is also found in many Western medical journals. In 2004, 8 years after publication of the CONSORT Statement (intended to improve the quality of reporting of results in random- ized controlled trials), more than 40% of trials published in Western medical journals failed to use

adequate randomization methods or failed to report the method for concealment of allocation.18 In 1994, this figure was as high as 70% to 80%.19

An additional comment on the issue of blinding in these studies is warranted. Most of the studies (20 of 26) assessed in this meta-analysis provided the treat- ment group with orally administered Chinese herbal medicine combined with intravenous chemotherapy and the control group only intravenous chemother- apy. Therefore, blinding of subjects and clinicians was not possible. In such a study design setting, blinding could be achieved only if the treatment and control groups received both oral and intravenous trial medi- cations (ie, the treatment group was given true orally administered herbal medicine and intravenous che- motherapy and the control group was given placebo orally administered herbal medicine and intravenous chemotherapy).

In future trials, we propose that Chinese investiga- tors employ relatively simple measures such as ran- dom number–generating software for use in

randomization and placebo trial drugs for use in com- paring different therapies or in evaluating new and emerging extracted active components of Chinese herbal medicines. More thorough reporting of patients’ characteristics and accounting for patient withdrawals and dropouts would also be helpful.

Standardized herbal formulas. Since there is no stan- dard Chinese formula for the treatment of HCC, it is hard to identify the active components in the treat- ments. Further investigation is needed on effects of Chinese herbal medicine on HCC, on the identity of active components of Chinese herbal medicine, and on the therapeutic mechanisms underlying possible survival benefits of combining Chinese herbal medicine with chemotherapy for HCC.

Acknowledgments
Administrative and methodological support provided by the Pine Street Foundation (San Anselmo, Calif; www.pinestreetfoundation.org).